Purpose:We investigated the presence of functional 1, 2 and 3-adrenoceptor in urothelium and detrusor muscle of Materials and Methods: Expression of these adrenoceptors in surgically separated human urothelium and detrusor muscle produced by Results:1, 2 and 3-adrenoceptor in both human urothelium and -adrenoceptors such as procaterol and isoproterenol evoked potent concentration-dependent relaxation of isolated human bladder strips with pD 2 Conclusions:site of actions for the

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75–21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88–154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30–40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk.

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The objective of the study was to evaluate the local effects of three antimuscarinics excreted into human urine after oral ingestion. Two normal adult collected their voided urine after taking oral doses of tolterodine, darifenacin, and solifenacin for 7 days with a 14-day washout period. The urodynamic effect of intravesically administered human urine on carbachol-induced bladder overactivity was studied in female rats. Cystometric parameters were measured during continuous infusion of saline and human urine and then a mixture of carbachol (30 microM) and human urine. Carbachol significantly reduced the intercontraction interval and bladder capacity in the control (urine taken in the absence of oral antimuscarinics) and tolterodine- or darifenacin-administered groups. However, human urine obtained after taking solifenacin prevented the carbachol-induced detrusor overactivity. Urine excreted after oral ingestion of solifenacin provides a localized pharmacological advantage for the treatment of the overactive bladder syndrome.

Background: Cotinine is a metabolite of nicotine. Serum and urinary cotinine are validated biomarkers for cigarette exposure. Their performance for lung cancer risk prediction has not been simultaneously examined in epidemiologic studies.Methods: A nested case-control study, including 452 incident lung cancer cases and 452 smoking-matched controls in the Shanghai cohort study, was conducted. Mass spectrometry-based methods were used to quantify cotinine in serum and urine samples collected from current smokers at baseline, on average 10 years before cancer diagnosis of cases. Logistic regression was used to estimate ORs, 95% confidence intervals (CI), and AUC ROC for lung cancer associated with higher levels of cotinine.Results: Serum and urinary cotinine levels were significantly higher in lung cancer cases than controls. Compared with the lowest quartile serum cotinine ( 0.40 nmol/mL), the OR of lung cancer for smokers in the highest quartiles (>1.39 nmol/mL) was 5.46 (95% CI, 3.38-8.81). Similarly, the OR was 5.49 (95% CI, 3.39-8.87) for highest (>16.38 nmol/mg creatinine) relative to the lowest quartile of urinary total cotinine ( 4.11 nmol/mg creatinine). A risk prediction model yielded an AUC of 0.72 (95% CI, 0.69-0.75) for serum cotinine and 0.72 (95% CI, 0.69-0.75) for urinary total cotinine combined with smoking history.Conclusions: Urinary and serum cotinine have the same performance in prediction of lung cancer risk for current smokers.Impact: Urinary cotinine is a noninvasive biomarker that can replace serum cotinine in risk prediction of future lung cancer risk for current smokers.

Background: While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) have been described previously, their combined impact on HCC risk is unknown. Methods: The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean diet, and sleep duration, and HCC risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese men and women. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI). Conditional logistic regression method was used to evaluate this composite lifestyle score–HCC risk association among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg) and anti–hepatitis C antibody. Results: After a mean follow-up of 17.7 years, 561 participants developed HCC. Individuals with higher composite scores representing healthier lifestyles (range 0–8) were at significantly lower risk of HCC. Compared with the lowest composite score category (0–4), the HRs (95% CIs) for the composite scores of 5, 6, 7, and 8 were 0.67 (0.62–0.85), 0.61 (0.48–0.77), 0.49 (0.37–0.65), and 0.13 (0.06–0.30), respectively (Ptrend < 0.0001). A similar inverse association was observed in participants with negative HBsAg and anti–hepatitis C virus (HCV)-negative serology (HR, 0.38; 95% CI, 0.19–0.79; for the highest vs. the lowest category of the composite scores; Ptrend = 0.001). Conclusions: Healthy lifestyles protect against HCC development, especially for individuals without hepatitis B virus and HCV infections. Impact: This study highlights the importance of a comprehensive lifestyle modification strategy for HCC primary prevention.

Background: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70-80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3’-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine metabolizing enzyme genes on urinary nicotine metabolites levels. Methods: Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data. Results: Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N’-oxide, a 6-fold increase in nicotine-Glucuronide, and a 5-fold decrease in 3HC-Glucuronide when comparing the lower vs upper 3HC/cotinine ventiles. Significant (p<0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Glucuronide, nicotine-N’-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Glucuronide and cotinine-Glucuronide, UGT2B17 genotype and levels of 3HC-Glucuronide, FMO3 genotype and levels of nicotine-N’-oxide, and CYP2B6 genotype and levels of nicotine-N’-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid. Conclusions: These data suggest that several pathways are important in nicotine metabolism. Impact: Genotype differences in several nicotine metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation

Background and Aim: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). Methods: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results: In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. Conclusions: SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.